Kinases are a class of enzyme that control the transfer of phosphate groups from phosphate donors, for example ATP, to specific substrates. Protein kinases are a subset of kinases and serine/threonine-protein kinase B-RAF is one such protein kinase. Serine/threonine-protein kinase B-RAF is more commonly known as B-RAF and throughout this application these two terms will be used interchangeably.
B-RAF is a member of the RAF kinase family, the other members of the family being A-RAF and C-RAF. Each of the RAF kinases is a serine/threonine-specific protein kinase, an enzyme that phosphorylates the hydroxyl group of serine or threonine residues within a protein. The RAF kinases are involved in the mitogen-activated protein kinase (MAPK) cascade, a key pathway involved in internal cell signalling responsible for cell division, cell proliferation, programmed cell death (apoptosis), cell differentiation, and embryonic development.
Defects in the MAPK pathway can affect the signalling within a cell and can lead to uncontrolled cell growth through deviant cell division and irregular cell death. Such defects in the MAPK pathway can be caused by mutations to the RAF kinases or aberrant expression of the RAF kinases, as such abnormalities associated with the RAF kinases, such as the known mutation B-RAFV600E can give rise to uncontrolled cell growth and consequently cancer.
Thus, controlling aberrant functioning of RAF kinases by small molecule inhibition presents a useful approach for the treatment of cancers.
A number of RAF inhibitors have been identified. Two such compounds are dabrafenib and vemurafenib. Dabrafenib is a B-RAF inhibitor indicated in the treatment of malignant melanoma and marketed by GlaxoSmithKline. Dabrafenib was approved for the treatment of malignant melanoma in May 2013 by the US FDA. Similarly, in August 2011 vemurafenib was approved for the treatment of melanoma by the US FDA. As with dabrafenib, vemurafenib is a B-RAF inhibitor, specifically of the B-RAFV600E mutation.
RAF inhibitors such as dabrafenib and vemurafenib have been approved for the treatment of unresectable and metastatic B-RAF-mutant melanoma, but these agents lack efficacy in B-RAF-mutant colorectal cancer (CRC), partly because of EGFR-mediated feedback reactivation of the MAPK pathway. Furthermore, RAF inhibitor treatment of RAS-mutant, B-RAFWT-melanomas has been associated with other skin cancers, such as cutaneous squamous cell carcinoma due to MAPK pathway paradoxical activation. There is therefore a clinical need for novel agents targeting the MAPK pathway that do not have the undesirable properties of EGFR-mediated feedback reactivation of the MAPK pathway and MAPK pathway paradoxical activation.
A number of patents have been published describing B-RAF inhibitors. One such publication is WO 2012/125981 which describes a compound having a structure related to dabrafenib. Both compounds contain a central 5-membered heterocycle flanked by two substituted 6-membered (or higher) ring systems. In addition to WO 2012/125981, B-RAF inhibitors have also been disclosed in WO 2012/016993, WO 2011/085269, WO 2011/025927, WO 2011/092088 and WO 2011/023773, for example.
In addition to these documents fused tricyclic compounds as RAF kinase inhibitors were recently disclosed in WO 2013/097224. In addition, US 2010/0197924 discloses aminotetralin compounds with kinase inhibitory activity, specifically RAF kinase inhibitory activity and WO 2007/067444 discloses bicyclic compounds for the same purpose.
It is an aim of certain embodiments of this invention to provide new cancer treatments. In particular, it is an aim of certain embodiments of this invention to provide compounds which have comparable activity to existing cancer treatments, ideally better activity.
Certain embodiments of this invention aim to provide for compounds which are suitable for the treatment of cancers which have been identified as containing a mutation of the BRAF kinase, for example human melanomas, thyroid cancer, Barret's adenocarcinoma, biliary tract carcinomas, breast cancer, cervical cancer, cholangiocarcinoma, central nervous system tumors, glioblastomas, astrocytomas, ependymomas, colorectal cancer, large intestine colon cancer, gastric cancer, carcinoma of the head and neck, hematologic cancers, leukaemia, acute lymphoblastic leukaemia, myelodysplastic syndromes, chronic myelogenous leukaemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukaemia, multiple myeloma, hepatocellular carcinoma, lung cancer, ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, renal cancer, sarcoma, uveal melanoma and skin cancer. Certain embodiments of this invention aim to provide for compounds which are suitable for the treatment of cancers which have been identified as containing the BRAFV600E mutation. For example BRAFV600E melanoma, BRAFV600E colorectal cancer, BRAFV600E papillary thyroid cancers, BRAFV600E low grade serous ovarian cancers, BRAFV600E glioma, BRAFV600E hepatobiliary cancers, BRAFV600E hairy cell leukaemia, BRAFV600E non-small cell cancer, and BRAFV600E pilocytic astrocytoma.
RAF inhibitor treatment of RAS-mutant, BRAFWT-melanomas has been associated with other skin cancers, such as cutaneous squamous cell carcinoma due to MAPK pathway paradoxical activation. There is therefore a clinical need for novel agents targeting the MAPK pathway that do not have these undesirable properties. Certain embodiments of this invention aim to provide compounds which show reduced side effects. For example, certain embodiments of this invention aim to provide for compounds which show reduced paradoxical activation of the MAPK pathway in BRAFWT cells and which inhibit the MAPK pathway at therapeutically relevant concentrations.
Certain embodiments of this invention aim to provide for compounds which show sustained MAPK pathway inhibition over 24 hours in cell lines known to undergo reactivation of the MAPK pathway following treatment with the RAF inhibitors dabrafenib and vemurafenib. Certain embodiments also aim to reduce paradoxical activation of MAPK pathway compared to dabrafenib and/or vemurafenib.
It is an aim of certain embodiments of this invention to provide compounds which exhibit reduced cytotoxicity relative to prior art compounds and existing therapies.
Another aim of certain embodiments of this invention is to provide compounds having a convenient pharmacokinetic profile and a suitable duration of action following dosing. A further aim of certain embodiments of this invention is to provide compounds in which the metabolised fragment or fragments of the drug after absorption are GRAS (Generally Regarded As Safe).
Certain embodiments of the present invention satisfy some or all of the above aims.